Abstract 12697: In vivo Expansion of Regulatory T Cells Attenuates Aortic Aneurysm Formation in Angiotensin II- Infused Apolipoprotein E-deficient Mice
Background: Recent studies have shown that pathogenic immune responses might be involved in the acceleration of abdominal aortic aneurysm (AAA) formation as well as atherosclerotic plaque development. Although regulatory T cells (Tregs) have been shown to play a protective role in atherogenesis by regulating inflammation, the role of Tregs in AAA formation remains completely unknown. In this study, we examined the effects of Treg expansion in an experimental model of AAA.
Methods and Results: We continuously infused 12-week-old apolipoprotein E-deficient mice fed a high-cholesterol diet with angiotensin II (1,000 ng/kg/min; n=51) or normal saline (n=8) for 4 weeks by implanting osmotic mini-pumps and evaluated the AAA formation at 16 weeks old. The angiotensin II-infused mice received IL-2/anti-IL-2 monoclonal antibody complexes (IL-2 complexes; 1 ug IL-2 plus 5 ug anti-IL-2 mAb) for in vivo Treg expansion (n=26) or phosphate buffered saline (n=25) on 3 consecutive days after which they received one dose weekly during angiotensin II infusion. There was no significant difference in systolic blood pressure between the 2 groups. Mice treated with IL-2 complexes showed expansion of Foxp3+ Tregs exhibiting an activated phenotype in lymph nodes and spleen. Angiotensin II infusion led to the development of AAA in 81% of the mice, with 38% mortality possibly from aneurysm rupture. IL-2 complexes treatment resulted in a significant decrease in the incidence of AAA (56%) and mortality (16%) in angiotensin II-infused mice. Immunohistochemical analysis showed a reduction in the accumulation of macrophages (p≤0.05) and an increase in the number of Foxp3+ Tregs (p≤0.05) in the aortic aneurysm tissue of IL-2 complexes-treated mice compared with control mice. Consistent with this, we detected a decrease in IFN-γ mRNA expression (p≤0.05) and an increase in Foxp3 mRNA expression (p≤0.05) in the aortic aneurysm tissue of IL-2 complexes-treated mice, suggesting that expanded Tregs may suppress local inflammation in the vessel wall, leading to a protection against AAA formation.
Conclusion: Our findings suggest that Tregs may play a protective role in AAA formation and that promotion of regulatory immune response may represent a novel therapeutic approach to AAA.
- © 2013 by American Heart Association, Inc.